Compounds of the secomacrolide and secoazalide class and a process for the preparation thereof

ABSTRACT

The present invention refers to the new compounds of the secomacrolide and secoazalide class, a process for the preparation thereof as well as to new intermediates for the preparation of these seco derivatives.

TECHNICAL FIELD

International Patent Classification: A 61 K 31/70, C 07 H 17/08

TECHNICAL PROBLEM

The present invention relates to new compounds of the secomacrolide andsecoazalide class, potential intermediates in the preparation of the newmacrolide and azalide antibiotics, as well as to a process for thepreparation thereof.

PRIOR ART

Erythromycin A is a valuable macrolide antibiotic, whose structure ischaracterized by 14-member lactone ring having a keto group at C-9position (McGuire, Antibiot. Chemother., 1952, 2:281). For more than 40years erythromycin A has been considered to be a safe and activeantimicrobial agent for treating gram-positive infections. The principaldisadvantages of the use of erythromycin A in human medicine are itsrestricted range of action against gram-negative bacterial strains; itsgastric intolerance with many patients and its loss of activity in anacidic medium with the formation of the inactive metaboliteanhydroerythromycin. The spirocyclization of the aglycone ring oferythromycin A is successfully inhibited by chemical transformation ofC-9 ketone or of hydroxyl groups at C-6 and/or C-12 position. Thus e.g.by oximation of C-9 ketone with hydroxylamine hydrochloride, followed byBeckmann's rearrangement of the obtained 9(E)-erythromycin A oxime andthe reduction of the thus formed bicyclic 6,9-imino ether, there wasobtained 9-deoxo-9a-aza-9a-homoerythromycin A, the first macrolidehaving a 15-membered azalactone ring (Kobrehel G. et al., U.S. Pat. No.4,328,334, May 1982). By reductive methylation of 9a-amino groupaccording to Eschweiler-Clark process,9-deoxo-9a-methyl-9a-aza-9a-homoerythromycin A (AZITHROMYCIN) (KobrehelG. et al., BE Pat. 892 357, July 1982), a prototype of new antibioticsof azalide class was synthesized. In addition to the broad antimicrobialrange including gram-negative bacteria and intracellular microorganisms,azithyromycin is also characterized by a specific transport mechanism tothe site of application, a long biological half-lite and a short therapyperiod.

Recently, the hydrolysis and alcoholysis of C-1 lactone of erythromycinA and B, whereby corresponding linear seco-acids or esters are formed(Martin S. F., J. Am. Chem. Soc., 1991, 113, 5478-5480), were described.Further, base catalyzed transformations, which lead to an opening of themacrocyclic ring under the formation of C-1 carboxylate (Waddel S. T.and Blizzard T. A., WO 94/15617, July 1994) were described. There hasalso been described the formation of new macrolide and azalide rings viaa combination of the east 8a-aza-(C-1/C-8) and 9a-aza-(C-1/C-9)fragments of 9-deoxo-8a-aza-8a-homoerythromycin A as well as9-deoxo-9a-aza-9a-homoerythromycin A with different fragments, whichbecome the west molecule part. It should be emphasized that theabove-mentioned obtained C-1/C-9 linear fragment differs from thecorresponding azythromycin fragment with regard to the additionalethylene group at C-9 carbon atom.

TECHNICAL SOLUTION

According to our knowledge of the prior art, there have not yet beendescribed linear 9a-azalide fragments of macrolide antibiotics ofazalide class of the general formula (I) ##STR1## wherein R₁ and R₂ arethe same and represent H or CH₃,

R₃ and R₄ are different and represent H or CH₃,

Y is O or NH, and

Z is CH₃ or the CH(CH₃)CH(OH)COH(CH₃)CH(OH)C₂ H₅ group,

or their pharmaceutically acceptable addition salts with inorganic ororganic acids. The substituents R₃ and R₄ characterize two epimere formsof the said compound of general formula (I), which only differstructurally in the configuration of the chiral centre at C-8 carbon.Even though the stereochemistry at C-8 carbon has not been established,to the compounds, wherein R₃ represents the CH₃ group, (R)-configurationis attributed on the basis of similarity of the chemical shifts of thesepounds and of the starting 6,9-amino other having C-8(R) configuration.

The present invention also relates to a process and to hitherto notdescribed intermediates for the preparation of the compounds of thegeneral formula (I). The structure of the intermediates is representedby the general formula (II), ##STR2## wherein X is O or NOR₇, wherein R₇is H, acyl or arylsulfonyl group,

R₃ and R₄ are different and represent H or CF₃,

R₅ and R₆ are the same or different and represent H or acyl group,

Y is O or NH and

Z is CH₃, a CH(C₂ H₅)COH(CH₃)CH(OR₈)CH(CH₃)NHR₉ orCH(CH₃)CH(OR₁₀)COH(CH₃)CH(OR₁₁)C₂ H₅ group,

R₈ is H or acyl group, and

R₉ is H, acylsulfonyl group, and

R₁₀ and R₁₁ are the same and represent H or acyl group.

The invention also relates to pharmaceutically acceptable addition saltsthereof with inorganic or organic acids.

Generally it can be said that at the new compounds of the generalformulas (I) and (II), the "east" part of the molecule including bothsugars is structuraIIy identical to the corresponding C-1/C-9 fragmentof the macrolactone ring of erythromycin A 6,9-imino ether or of9-deoxo-9a-aza-9a-homoerythromycin A, whereas the "west" part representsC-1 methylester group or unsubstituted or substituted C-10/C-15 fragmentof the starting imino ether with terminal unsubstituted or substitutedprimary group, or represents the same fragment inversively bound to C-1atom, yielding, instead of C-1 lactone, new, hitherto not yet describedC-1 amides.

Compounds according to general formula (I) of the present invention canbe reacted to provide the corresponding azalide compounds using standardreactions, such as described in the literature including J. March,Advanced Organic Chemistry, Reactions, Mechanisms and Structure, J.Wiley & Sons, Inc., III ed., 1985, pp. 366-368, disclosure of which isincorporated herein by reference.

Since the azalide compounds obtainable from compounds according togeneral formula (I) will have the same "eastern side" of the molecule asthe azalides described in WO 94/15617 but will differ in the "westernside," it will be apparent to persons skilled in the art that theazalide compounds obtainable from intermediates according to the presentinvention will exhibit antibacterial action.

For example, from WO 94/15617, it is evident that numerous modificationsin the "western side" of the molecule did not cause a decrease of thebiological activity of the compounds, therefore, it can be concludedthat this part of the molecule is not decisive for the antimicrobicproperties.

As stated above, azalide compounds obtainable from intermediatesaccording to the present invention differ just in this "western side" ofthe molecule, which is unimportant for its antibacterial action.Therefore, the present invention can be used by those skilled in the artwithout undue experimentation. The disclosure of WO 94/15617 isincorporated herein by reference.

However, the azalide compounds of WO 94/15617 are obtained fromessentially different intermediates and by the use of a different typeof chemical reactions than those of the present invention, thereforebetween the present application and WO 94/15617 there exists anessential difference in intermediates, as well as in chemical processesfor obtaining the corresponding azalide compounds.

New 9a-azalide fragments of the general formula (I) ##STR3## wherein R₁and R₂ are the same and represent H or CH₃,

R₃ and R₄ are different and represent H or CH₃,

Y is O or NH, and

Z is CH₃ or CH(CH₃)CH(OH)COH(CH₃)CH(OH)C₂ H₅ group,

and their pharmaceutically acceptable addition salts with inorganic ororganic acids are obtained by a process, wherein the startingerythromycin A 6,9-imino ether of the formula (III), ##STR4## issubjected A) to the action of an acid under the conditions of thehydrolysis of the imino group and then, if appropriate, to N- and/orO-acylation with acid anhydrides or chlorides and then, if appropriate,to solvolysis, or

B) to the reaction with hydroxylamine hydrochloride in the presence ofappropriate inorganic or organic bases in one or two reaction steps andthen, if appropriate,

B1) to the action of appropriate inorganic or organic acids under theconditions of the hydrolysis of the hydroxyimino group and then, ifappropriate, to N- and/or O-acylation and then to solvolysis asdescribed under A) or, if appropriate,

B2) to N- and/or O-acylation with acid arthydrides and chlorides andthen, if appropriate, to solvolysis or, if appropriate,

B3) to the action of appropriate organic or inorganic bases under theconditions of internal amine acylation and then, if appropriate, to N-and/or O-acylation with acid anhydrides or chlorides and then, ffappropriate, to solvolysis, yielding compounds of the general formula(II), ##STR5## wherein X is O or NOR₇, wherein R₇ is H, acyl orarylsulfonyl group,

R₃ and R₄ are different and represent H or CH₃,

R₅ and R₆ are the same or different and represent H or acyl group,

Y is O or NH, and

Z is CH₃, CH(C₂ H₅)COH(CH₃)CH(OR₈)CH(CH₃)NHR₉ orCH(CH₃)CH(OR₁₀)COH(CH₃)CH(OR₁₁)C₂ H₅ group,

R₈ is H or acyl group,

R₉ is H, acyl or arylsulfonyl group, and

R₁₀ and R₁₁ are the same and represent H or acyl group,

and their pharmaceutically acceptable addition salts with inorganic ororganic acids, which, if appropriate, are subjected to catalyticreduction and then, if appropriate, to reductive N-alkylation withappropriate alkylation agents in the presence of appropriate reductiveagents, yielding compounds of the general formula (I), wherein R₁, R₂,R₃, R₄, Y and Z have the above-mentioned meanings. The preparation ofthe new compounds of the general formula (I) and (II) can be representedby reaction schemes 1 and 2.

The compound of the general formula (II), wherein X and Y are the sameand represent O, R₃ is CH₃ and R₄ is H, R₅ and R₆ are the same andrepresent H, Z is CH(C₂ H₅)COH(CH₃)CH(OR₈)CH(CH₃)NHR₉, wherein R₈ and R₉are the same and represent H (Scheme 1, 2a) is obtained according to themethod A) by the action of an acid, preferably glacial acetic acid, uponerythromycin A 6,9-imino ether of formula (III) under the conditions ofimine hydrolysis at room temperature within 3 days, whereby C-9/9a-Nbond is cleaved, or by the action of inorganic or organic acids underthe conditions of hydrolysis of hydroxyimino group upon the compound ofthe general formula (II) obtained according to the method B), wherein Xis NOR₇, wherein R₇ is H, R₃ is CH₃ and R₄ is H, R₅ and R₆ are the sameand represent H, Y is O and Z is CH(C₂ H₅)COH(CH₃)CH(OR₈)CH(CH₃)NHR₉,wherein R₈ and R₉ are the same and represent H. Preferably, thehydrolysis of hydroxyimino group is performed by standing in a mixtureof methanol/HCl at room temperature for 10 days. The obtained producthaving the new 5-membered lactone ring is isolated by means of a commongradient extraction process (pH 5.5, 6.5 and 8.3) followed by theevaporation of the combined organic extracts at pH 8.3 and issubsequently, if appropriate, subjected to N- and/or O-acylation withacid anhydrides or chlorides.

The acylation reaction of the obtained lactone with an acid anhydride isperformed by a common process (Jones et al., J. Med. Chem., 1971, 5:631and Banaszek et al., Rocy. Chem., 1969, 43:763), yielding thecorresponding tetraalkanoyl derivatives. Thus e.g. by acylation withacetic acid anhydride in solvent inert to the reaction, preferably inpyridine, at room temperature within 7 days,2',4",11-O,10-N-tetra-acetate of the general formula (II) is obtained,wherein X and Y are the same and represent O, R₃ is CH₃ and R₄ is H, R₅and R₆ are the same and represent COCH₃, Z is CH(C₂H₅)COH(CH₃)CH(OR₈)CH(CH₃)NHR₉, wherein R₈ and R₉ are the same andrepresent COCH₃ (Compound 2b). By standing 2',4",11-O,10-N-tetra-acetatein methanol at room temperature within 3 days and solvolysis of theester group in 2'-position, 4",11-O,10-N-triacetate of the generalformula (II) is formed, wherein R₅ is H and X, Y, Z, R₃, R₄, R₆, R₈ andR₉ have the meanings mentioned above at tetraacetate (Compound 2c). Theacylation with acid chloride, preferably with 4-bromobenzoyl chloride isperformed in a solvent inert to the reaction, preferably indiethylether, at a temperature from 0° C. to 5° C. within 3 hours,yielding 10-N-bromobenzoyl derivative of the general formula (II),wherein X and Y are the same and represent O, R₃ is CH₃ and R₄ is H, R₅and R₆ are the same and represent H, Z is CH(C₂H₅)COH(CH₃)CH(OR₈)CH(CH₃)NHR₉, wherein R₈ is H and R₉ is 4-bromo-benzoylgroup (Compound 2d).

The reaction of erythromycin A 6,9-imino ether of formula (III) withhydroxylamine hydrochloride is performed according to the method B) in asolvent inert to the reaction, in the presence of inorganic or organicbases, in one or two reaction steps at a temperature from 25° to 70° C.By performing the reaction in one step, a cleavage of C-9/9a-N bondunder the formation of the hydroxylimino group at C-9 atom and of aprimary amino group at C-10 atom occurs, yielding the compound of thegeneral formula (II), wherein X is NOR₇, wherein R₇ is H, Y is O, R₃ isCH₃ and R₄ is H, R₅ and R₆ are the same and represent H, and Z is CH(C₂H₅)COH(CH₃)CH(OR₈)CH(CH₃)NHR₉ group, wherein R₈ and R₉ are the same andrepresent H, as the only product (Scheme 1, 3a). The reaction isperformed with a 1.1 to 30 molar excess of hydroxylamine hydrochloride,preferably with a 5.2 molar excess. Typical solvents inert to thereaction are C₁ -C₄ alcohols, preferably methanol. As acid acceptorsthere may be used inorganic bases such as alkali metal carbonates orhydrogencarbonates, preferably sodium carbonate or potassium carbonate,or organic bases such as pyridine, which at the same time also act assolvents inert to the reaction. The isolation is performed by the use ofthe common extraction process with organic solvents, preferablychlorinated hydrocarbons, preferably methylenechloride at pH 10. If thereaction is performed in two steps, i.e. in the first reaction steperythromycin A 6,9-imino ether of formula (III) is subjected to theaction of an at least 1.3 molar excess of the above described inorganicor organic bases in a solvent inert to the reaction, preferably in C₁-C₄ -alcohols, preferably in methanol, under the reflux stream of thereaction mixture until imino ether disappears (TLC), then the obtainedproduct mixture is isolated by an extraction process, preferably withchlorinated hydrocarbons, preferably with methylenechloride at pH 8 andthen in the second step the crude product is subjected to the action ofhydroxylamine hydrochloride in the presence of inorganic or organicbases as described above, the reaction is not unambiguous. The obtainedproduct mixture is isolated by gradient extraction with organicsolvents, preferably with methylenechloride at pH 8 and 10. Byconcentrating the combined organic extracts at pH 10, a mixture of twoproducts is obtained, one of which is identical to the compound (3a) andthe other is its C-8(S)-enantiomer of the general formula (II), whereinX is NOR₇, wherein R₇ is H, Y is O, R₃ is H and R₄ is CH₃, R₅ and R₆ arethe same and represent H, and Z is CH(C₂ H₅)COH(CH₃)CH(OR₈)CH(CH₃)NHR₉group, wherein R₈ and R₉ are the same and represent H (Scheme 2, 3b). Byevaporating the combined organic extracts at pH 8, in addition to thecompounds (3a) and (3b), there are also obtained two isomeric C-8 oximesof the general formula (II), wherein X is NOR₇, wherein R₇ is H, Y is O,R₃ and R₄ are different and represent H or CH₃ group, R₅ and R₆ are thesame and represent H, and Z is CH₃ (Scheme 2, 7a and 7b) as a result ofsimultaneous cleaving of the C-9/9a-N bond and of the macrocyclic C-1lactone under the formation of C-1 metoxylate. The obtained compounds(7a) and (7b) are separated by chromatography on silica gel column usinga 6:1:0.1 CHCl₃ :CH₃ OH:conc. NH₄ OH system and then, if appropriate,subjected to catalytic reduction.

Oximes (3a) and (3b) with terminal amino group are subjected, ifappropriate, to N- and/or O-acylation with acid anhydrides and chloridesas described in method A) and then, if appropriate, to solvolysis. Thuse.g. by acylation of compound (3a) with acetic acid anhydride, there isobtained 2',4",11-O,10-N-tetraacetyl 9(E)-acetoxime of the generalformula (II), wherein X is NOR₇, wherein R₇ is COCH₃ group, R₃ is CH₃and R₄ is H, R₅ and R₆ are the same and represent COCH₃, Y is O and Z isCH(C₂ H₅)COH(CH₃)CH(OR₈)CH(CH₃)NHR₉ group, wherein R₈ and R₉ are thesame and represent COCH₃ (Compound 3c), which, if appropriate, issubjected to solvolysis, preferably methanolysis, yielding the compoundof the general formula (II), wherein X is NOR₇, wherein R₇ is H, R₃ isCH₃ and R₄ and R₅ are the same and represent H, R₆ is COCH₃, Y is O andZ is CH(C₂ H₅)COH(CH₃)CH(OR₈)CH(CH₃)NHR₉ group, wherein R₈ and R₉ arethe same and represent COCH₃ (Compound 3d). By reacting compounds (3a)and (3b) with acid chlorides in a solvent inert to the reaction in thepresence of inorganic or organic bases at a temperature from 0° C. to25° C. mono- and disubstituted acyl derivatives are obtained, which, ifappropriate, are separated by chromatography on silica gel column by theuse of 85:15 CH₂ Cl₂ :CH₃ OH solvent system. Preferably, by reactingcompound (3a) with tosylchloride in the presence of NaHCO₃ in acetonewithin 3 hours there are obtained compounds of the general formula (II),wherein X is NOR₇, wherein R₇ is tosyl, R₃ is CH₃ and R₄, R₅ and R₆ arethe same and represent H, Y is O and Z is CH(C₂H₅)COH(CH₃)CH(OR₈)CH(CH₃)NHR₉ group, wherein R₈ is H and R₉ is tosyl(Compound 3e) or wherein X is NOR₇, wherein R₇ is H, R₃ is CH₃ and R₄,R₅ and R₆ are the same and represent H, Y is O and Z is CH(C₂H₅)COH(CH₃)CH(OR₈)CH(CH₃)NHR₉ group, wherein R₈ is H and R₉ is tosyl(Compound 3f).

If appropriate, compounds (3a) and (3b) arc subjected to the action ofbases under the conditions of internal amine acytation and then, ifappropriate, to catalytic reduction. The internal acylation reaction ofthe above primary amines is performed at room temperature in thepresence of inorganic and organic bases, preferably ammonium hydroxide,potassium or sodium hydroxide or triethylamine, whereat an internalmigration of C-1 acyloxy group from oxygen to the terminal amino groupoccurs, giving rise to the inversion of C-10/C-15 west molecule fragmentand to the formation of C-1 amide of the general formula (II), wherein Xis NOR₇, wherein R₇ is H, R₃ and R₄ are different and represent H orCH₃, R₅ and R₆ are the same and represent H, Y is NH and Z isCH(CH₃)CH(OR₁₀)COH(CH₃)CH(OR₁₁)C₂ H₅ group, wherein R₁₀ and R₁₁ are thesame and represent H (Scheme 2, 4a and 4b), which, if appropriate, aresubjeered to N- and/or O-acylation with acid anhydrides or chlorides or,if appropriate, to catalytic reduction.

The reaction of N- and/or O-acylation of compounds (4a) and (4b) withacid anhydrides according to method A) yields2',4"-O-diacyl-1N-(2,4-O-diacyl)-9(E)acyloxime. Thus e.g. by acylationof compound (4a) with acetic acid anhydride in pyridine at roomtemperature within 10 days, a compound of the general formula (II) isobtained, wherein X is NOR₇, wherein R₇ is COCH₃ group, R₃ is CH₃ and R₄is H, R₅ and R₆ are the same and represent COCH₃, Y is NH and Z isCH(CH₃)CH(OR₁₀)COH(CH₃)CH(OR₁₁)C₂ H₅ group, wherein R₁₀ and R₁₁ are thesame and represent COCH₃ (Compound 4c). If appropriate, the compound(4c) is subjected to solvolysis, preferably methanolysis, whereat adeacylation of 2'-position or of 2'- and 9-oximester group occurs,yielding compounds of the general formula (II), wherein X is NOR₇,wherein R₇ is COCH₃ -group, R₃ is CH₃ and R₄ is H, R₅ is H, R₆represents COCH₃, Y is NH and Z is CH(CH₃)CH(OR₁₀) COH(CH₃)CH(OR₁₁)C₂ H₅group, wherein R₁₀ and R₁₁ are the same and represent COCH₃ (Compound4d), or X is NOR₇ wherein R₇ is H, R₃ is CH₃ and R₄ is H, R₅ is H, R₆ isCOCH₃, Y is NH and Z is CH(CH₃)CH(OR₁₀)COH(CH₃)CH(OR₁₁)C₂ H₅ group,wherein R₁₀ and R₁₁ are the same and represent COCH₃ (Compound 4e).Analogously to the tosyl derivatives (3e) and (3f) also monosubstitutedacyl derivatives are obtained by the reaction with acid chlorides.Preferably, by the reaction of (4a) with tosyl chloride in acetone inthe presence of NaHCO₃ at room temperature with 12 hours, the tosylderivative of the general formula (II) is obtained, wherein X is NOR₇,wherein R₇ is tosyl, R₃ is CH₃, R₄, R₅ and R₆ represent H, Y is NH and Zis CH(CH₃)CH(OR₁₀)COH(CH₃)CH(OR₁₁)C₂ H₅ group, wherein R₁₀ and R₁₁ arethe same and represent H (Compound 4f).

Catalytic reduction of the above stated oximes (4a, 4b, 7a, and 7b) isperformed in a solvent inert to the reaction in the presence of noblemetals or their oxides as catalysts at room temperature and at ahydrogen pressure from 5×10⁵ to 7×10⁶ Pa from 10 hours to 3 days.Preferably, the reduction is performed in glacial acetic acid by the useof platinum (IV) oxide as a catalyst within 10 hours at a hydrogenpressure of 7×10⁶ Pa, thereafter the product is isolated by the commongradient extraction process (pH 5.5, 9.0 and 10.5) with chlorinatedhydrocarbon, preferably chloroform, followed by the evaporation of thecombined organic extracts at pH 10.5. The obtained amines of the generalformula (I), wherein R₁ and R₂ are the same and represent H, R₃ is CH₃,R₄ is H, or R₃ H and R₄ is CH₃, Y is O or NH and Z is CH₃ orCH(CH₃)CH(OH)COH(CH₃)CH(OH)C₂ H₅ group (Scheme 2, 5a, 5b, 8a, and 8b),are, if appropriate, subjected to reductive N-alkylation. Preferably,the reductive N-methylation is performed with 1 to 4 equivalents offormaldehyde (37%) in the presence of the same or double quantity offormic acid (98-100%) in a solvent inert to the reaction such ashalogenated hydrocarbons, preferably in chloroform at reflux temperatureof the reaction mixture within 2 to 20 hours, which depends upon thequantity of the used aldehyde or acid. The obtained product is isolatedby the common gradient extraction process (pH 5.0 and 9.5) followed bythe evaporation of the combined organic extracts at pH 9.5 and, ifappropriate, it is purified by chromatography on a silica gel column bythe use of 6:1:0.1 CHCl₃ :CH₃ OH:conc. NH₄ OH system yieldingdimethylamino derivatives of the general formula (I), wherein R₁ and R₂are the same and represent CH₃, R₃ is CH₃ and R₄ is H, or R₃ is H and R₄is CH₃, Y is O or NH and Z is CH₃ or CH(CH₃)CH(OH)COH(CH₃)CH(OH)C₂ H₅group (Scheme 2, 6a, 6b, 9a, and 9b).

Pharmaceutically acceptable addition salts, which are also an object ofthe present invention, are obtained by the reaction of seco derivativesof the general formulas (I) and (II) with at least an equimolar amountof appropriate inorganic or organic acids such as hydrochloric acid,hydroiodic acid, sulfuric acid, phosphoric acid, acetic acid, propionicacid, trifluoroacetic acid, maleic acid, citric acid, stearic acid,succinic acid, ethylsuccinic acid, methanesulfonic acid, benzenesulfonicacid, p-toluenesulfonic acid, laurylsufonic acid etc. in a solvent inertthe reaction. The addition salts are isolated by filtration if they areinsoluble in the solvent inert to the reaction, by the precipitationwith a non-solvent or by the evaporation of the solvent, mostly by thelyophilization process.

By performing the reactions according to the aforesaid steps, an openingof the 15-membered azalactone ring of erythromycin A 6,9-imino etheroccurs, yielding seco derivatives with different very reactive terminalfunctional groups, which also makes possible the preparation of a wholeseries of new macrolides or azalides with modified macrocyclic aglycone.At the compounds with an inversion of the "west" part of the molecule(4, 5 and 6), 2,3,4-trihydroxy-1,3-dimethyl-hexyl group represents theC-10/C-15 fragment of erythromycin A 6,9-imino ether, wherein for thesake of simplicity the position designations of carbon atoms existingprior to the inversion of the fragment have been kept at stating thespectroscopic data. These designations are represented in Schemes 1 and2. ##STR6##

The following examples are intended only to illustrate the presentprocess and not to limit the scope of the invention.

EXAMPLE 19-deoxo-6-deoxy-6,9-epoxy-8(R)-methyl-10-amino-9,10-secoerythromycinA9(E)-oxime (3a) Method A

To an erythromycin A 6,9-iminoether solution (1) (36.0 g, 0.049 mole) inCH₃ OH abs. (750 ml), NH₂ OH HCl (18 g, 0.259 mole) and Na₂ CO₃ (6.8 g,0.0642 mole) were added and then the reaction mixture was stirred underreflux for 3 hours. The reaction suspension was evaporated at reducedpressure and to the solid residue 240 ml H₂ O and 240 ml CH₂ Cl₂ (pH6.8) were added. The pH was adjusted to 10 by the addition of 20% w/vNaOH and the aqueous part was repeatedly extracted with CH₂ Cl₂. Afterdrying over K₂ CO₃ the combined organic extracts were evaporated todryness and the obtained product was dried in high vacuum (6 hours, 40°C.) yielding 34.3 g (91%) of TLC homogeneous substance (3a).

IR (CHCl₃) cm⁻¹ : 3425, 2970, 1720, 1690, 1580, 1455, 1380, 1300, 1260,1165, 1050. ¹ H NMR (300 MHz, CDCl₃) δ: 4.98 (H-1"), 4.78 (H-13), 4.45(H-1'), 4.60 (H-3), 3.90 (H-5), 3.49 (H-11), 3.28 (3"-OCH₃), 3.05(H-10), 2.92 (H-8), 2.84 (H-2), 2.28 /3'N(CH₃)₂ /, 2.08 (H-7a), 1.88(H-7b), 1.87 (H-14a), 1.82 (H-4), 1.51 (H-14b), 0.87 (H-15). ¹³ C NMR(75 MHz, CDCl₃) δ: 175.5 (C-1), 161.1 (C-9), 103.1 (C-1'), 95.0 (C-1"),88.5 (C-6), 81.9 (C-5), 78.1 (C-13), 76.7 (C-3), 73.5 (C-12), 72.5(C-11), 48.7 (3"-OCH₃), 46.7 (C-10), 43.4 (C-2), 39.8/3'N(CH₃)₂ /, 39.7(C-4), 31.9 (C-8), 21.3 (C-14), 10.6 (C-15). FAB (MH⁺) 764.4.

Method B

To an erythromycin A 6,9-imino ether solution (1) (36.0 g, 0.049 mole)in pyridine (100 ml), NH₂ OH HCl (18 g, 0.259 mole) was added and thenthe reaction mixture was stirred for 3 hours at room temperature. To thereaction solution H₂ O (400 ml) and CH₂ Cl₂ (140 ml) were added and theproduct was isolated by gradient extraction at pH 7.0 and 10.0. Byevaporating the combined organic extracts at pH 10.0, 25.0 g (66.4%) ofa product (3a) with the identical physical-chemical constants asdescribed at Method A were obtained.

EXAMPLE 2

2',4",11-O,10-N-tetraacetyl-9-deoxo-6-deoxy-6,9-epoxy-8(R)-methyl-10-amino-9,10-secoerythromycinA 9(E)-acetoxime (3c)

To a solution of (3a)(1.0 g, 0.0013 mole) in pyridine (40 ml), aceticacid anhydride (4 ml) was added and then the reaction solution was leftto stand for 7 days at room temperature. After completed acetylation(TLC) it was poured into a mixture of water and ice (200 ml) andextracted with CHCl₃ at pH 9.0. The combined organic extracts wereevaporated at a reduced pressure yielding 1.3 g of a crude product,wherefrom after re-precipitation from an ether-petroleum ether mixture1.13 g of a TLC homogeneous product (3c) were obtained.

¹ H NMR (300 MHz, CDCl3) δ: 6.15 (CONH), 4.97 (H-13), 4.81 (H-2'), 4.78(H-1"), 4.69 (H-4"), 4.67 (H-11), 4.48 (H-10), 4.59 (H-1'), 4.11 (H-3),3.79 (H-5), 3.30 (H-3"-OCH₃), 3.14 (H-8), 2.75 (H-2), 2.27/3'N(CH₃)₂ /,2.16, 2.13, 2.12, 2.05 and 1.96 (COCH₃), 1.90 (H-4), 1.52 (H-14), 0.90(H-15).

EXAMPLE 34",11-O,10-N-triacetyl-9-deoxo-6-deoxy-6,9-epoxy-8(R)-methyl-10-amino-9,10-secoerythromycinA 9(E)-oxime (3d)

A pentaacetate solution (3c) (0.5 g, 0.0005 mole) in methanol (20 ml)was left to stand for 3 days at room temperature. The reaction mixturewas evaporated at a reduced pressure and the obtained crude product waspurified by chromatography on silica gel column by the use of 90:9:1.5CHCl₃ :CH₃ OH:conc. NH₄ OH system yielding 0.250 g of4",11-O,10-N-triacetate (3d) with the following physical-chemicalconstants:

¹ H NMR (300 MHz, CDCl₃) δ: 6.31 (CONH), 4.95 (H-13), 4.85 (H-1"), 4.67(H-4"), 4.65 (H-11), 4.49 (H-10), 4.49 (H-1'), 4.21 (H-3), 3.79 (H-5),3.29 (H-3"-OCH₃), 3.28 (H-2'), 3.02 (H-8), 2.78 (H-2), 2.30/3'N(CH₃)₂ /,2.17, 2.13, and 1.96 (COCH₃), 2.07 (H-7a), 2.02 (H-4), 1.85 (H-14a),1.49 (H-14b), 0.88 (H-15). ¹³ C NMR (75 MHz, CDCl₃) δ: 175.0 (C-1),172.0, 170.7 and 169.3 (COCH₃, 162.1 (C-9), 103.5 (C-1'), 95.5 (C-1"),89.6 (C-6), 81.2 (C-5), 78.3 (C-11), 78.1 (C-3), 76.8 (C-13), 74.9(C-12), 49.3 (3'-OCH₃), 45.0 (C-10), 42.5 (C-2), 40.1/3'N(CH₃)₂ /, 39.5(C-7), 38.4 (C-4), 32.7 (C-8), 23.1, 20.6 and 20.6 (COCH₃), 21.9 (C-14),10.7 (C-15).

EXAMPLE 49-O,10-N-ditosyl-9-deoxo-6-deoxy-6,9-epoxy-8(R)-methyl-10-amino-9,10-secoerythromycinA 9(E)-oxime (3e)10-N-tosyl-9-deoxo-6-deoxy-6,9-epoxy-8(R)-methyl-10-amino-9,10-secoerythromycinA 9(E)-oxime (3f)

The substance (3a)(2.0 g, 0.0026 mole) from Example 1 was suspended in70 ml of acetone and cooled to 0°-5° C. To the reaction mixturesolutions of tosyl chloride (1.34 g, 0.007 mole) in acetone (30 ml) andNaHCO₃ (0.6 g, 0.007 mole) in water (95 ml) were simultaneously addeddropwise under stirring within 30 minutes. The reaction suspension wasstirred for further 3 hours at room temperature, then acetone wasevaporated at a reduced pressure and the aqueous residue was extractedwith CHCl₃ at pH 5.0. After drying over K₂ CO₃ and evaporation of CHCl₃,2.58 g of product mixture of (3e) and (3f) were obtained. Bychromatography of the crude product (1.8 g) on silica gel column by theuse of 85:15 CH₂ Cl₂ :CH₃ OH, 0.250 g of TLC pure (CHCl₃ :CH₃ OH, 7:3)compound (3e) with Rf 0.63 and 1.1 g of compound (3f) with Rf 0.43 wereobtained.

Compound (3e)

IR (CHCl₃) cm⁻¹ : 3460, 2975, 2940, 1730, 1660, 1600, 1455, 1370, 1190,1180, 1160, 1090, 1050, 1000, 975, 855, 815, 665. ¹ NMR (300 MHz, CDCl₃)δ: 7.80 (p-Ph), 7.30 (p-Ph), 4.81 (H-13), 4.78 (H-1"), 4.48 (H-1'), 4.26(H-3), 3.96 (H-5"), 3.76 (H-5), 3.68 (H-5'), 3.60 (H-11), 3.50 (H-10),3.41 (H-2'), 3.23 (3"-OCH₃), 3.09 (H-8), 3.03 (H-4"), 2.94 (H-2),2.54/3'N(CH₃)₂ /, 2.43 (p-Ph-CH₃), 2.41 (p-Ph-CH₃), 2.24 (H-7a), 2.09(H-7b), 1.91 (H-4), 1.83 (H-4'a), 1.68 (H-14a), 1.52 (H-2"b), 1.41(H-14b), 1.49 (6-CH₃), 0.89 (H-15).

Compound (3f)

¹ H NMR (300 MHz, CDCl₃) δ7.43 (p-Ph), 7.14 (SO₂ NH), 4.91 (H-13), 4.78(H-1"), 4.60 (H-1'), 4.36 (H-3), 4.00 (H-5"), 3.82 (H-5), 3.73 (H-10),3.68 (H-5'), 3.64 (H-11), 3.41 (H-2'), 3.28 (3"-OCH-₃), 3.08 (H-8), 3.00(H-4"), 2.79 (H-2), 2.39 (p-Ph-CH₃), 2.24 (H-2"), 1.73 (H-14a), 1.52(6-CH₃), 0.85 (H-15).

EXAMPLE 5 6-Deoxy-6,9-epoxy-8(R)-methyl-10-amino-9,10-secoerythromycin A(2a) Method A

An erythromycin A 6,9-imino ether solution (1) (10.0 g, 0.014 mole) inglacial acetic acid (60 ml) was left to stand for 3 days at roomtemperature. The solvent was evaporated at a reduced pressure and thenwater (100 ml) was added to the oily residue and the reaction mixturewas extracted with CHCl₃ at pH 5.5, 6.5 and 8.3. After drying over K₂CO₃ the combined organic extracts at pH 8.3 were evaporated to drynessand the obtained product was dried in a high vacuum (6 hours, 40° C.),whereupon 8.2 g (80.0%) of TLC homogeneous product (2a) were obtained.

IR (CHCl₃) cm⁻¹ : 1740 (C-1, lactone) and 1710 (C-9, lactone). ¹ H NMR(300 MHz, CDCl₃) δ: 4.77 (H-1"), 5.00 (H-13), 4.39 (H-1'), 4.18 (H-3),3.74 (H-5), 3.35 (H-11), 3.29 (H-3"-OCH₃), 3.16 (H-10), 2.76 (H-8), 2.72(H-2), 2.29/3'N(CH₃)₂ /, 2.22 (H-7a), 2.10 (H-7b), 2.00 (H-4), 1.85(H-14a), 1.55 (H-14b), 0.88 (H-15). ¹³ C NMR, (75 MHz, CDCl₃) δ: 179.6(C-1), 176.1 (C-9), 103.9 (C-1'), 95.7 (C-1"), 86.1 (C-6), 81.2 (C-5),78.8 (C-13), 77.9 (C-3), 75.7 (C-11), 74.5 (C-12), 49.5 (3"-OCH₃), 47.9(C-10), 43.2 (C-2), 40.4/3'N(CH₃)₂ /, 39.7 (C-4), 38.0 (C-7), 34.1(C-8), 22.2 (C-14, 11.6 (C-15). EI-MS (M⁺) 748.

Method B

A solution of (3a) (2.0 g, 0.0026 mole) in methanol (30 ml) wasacidified with 1N HCl to pH 3.0 and left to stand for 10 days at roomtemperature. The pH of reaction mixture was adjusted to 7.0 with 10%NaOH, methanol was evaporated at a reduced pressure, to the aqueousresidue CHCl₃ was added and then it was extracted at pH 5.5, 6.5 and8.3. After drying ever K₂ CO₃ the combined organic extracted at pH 8.3were evaporated to dryness, yielding the product (2a) with the identicalphysical-chemical constants as described at Method A.

EXAMPLE 6 2', 4",11-O,10-N-tetraacetyl-6-deoxy-6,9-epoxy-8(R)-methyl-10-amino-9,10-secoerythromycin A (2b)

To a solution of (2a)(3.4 g, 0.0045 mole) in pyridine (45 ml), aceticacid anhydride (12 ml) was aded and it was left to stand for 7 days atroom temperature. After completed acetylation reaction (TLC), thereaction mixture was poured onto ice (200 ml) and extracted with CHCl₃at pH 9.0. The combined organic extracts were washed with saturatedNaHCO₃ solution and water, dried over K₂ CO₃ and evaporated at a reducedpressure. The obtained crude residue was dried in a high vacuum (6hours, 40° C.) yielding 4.10 g (98.0 %) of chromatographicallyhomogeneous product (2b).

IR (CHCl₃) cm⁻¹ : 1740 (C-1, lactone), 1720 (C-6, lactone), 1720 and1240 (C═O, ester), 1655 (C═O, amide). ¹ H NMR (300 MHz, CDCl₃) δ: 6.35(CONH), 4.99 (H-13), 4.79 (H-1"), 4.79 (H-2'), 4.68 (H-11), 4.62 (H-1'),4.44 (H-10), 4.14 (H-3), 3.76 (H-5), 3.32 (H-3"-OCH₃), 2.74 (H-8), 2.65(H-2), 2.28 /3'N(CH₃)₂ /, 2.10, 2.06, 2.03 and 1.92 (COCH₃), 2.08(H-7a), 1.96 (H-7b), 1.90 (H-4), 1.81 (H-14a), 1.60 (H-14b), 0.86(H-15). ⁻⁻ C NMR (75 MHz, CDCl₃) δ:179.3 (C-1), 174.7 (C-9), 171.9170.5, 169.9 and 169.2 (COCH₃). EI-MS (M⁺) 916.

EXAMPLE 7 4",11-O,10 -N-triacetyl-6-deoxy-6,9-epoxy-8(R)-methyl-10-amino-9,10-secoerythromycin A (2c)

A solution of (2b) (1.5 g, 0.0016 mole) in methanol (40 ml) was left tostand for 3 days at room temperature. The reaction mixture wasevaporated at reduced pressure and the obtained oily residue wasdissolved in CH₂ Cl₂ (50 ml), then 100 ml of water were added (pH 6.6)and the pH of the reaction mixture was adjusted to 9.0 with 10% w/vNaOH. The layers were separated and the aqueous part was extracted twomore times with CH₂ Cl₂. After the drying of the combined organicextracts over K₂ CO₃ and evaporation of the solvent at a reducedpressure, there were obtained 1.35 g of a crude product, which waspurified by chromatography on silica get column by the use of 6:1:0.1CHCl₃ :CH₃ OH:conc. NH₄ OH system yielding TLC homogeneous triacetate(2c) with the following physical-chemical constants:

¹ H NMR (300 MHz, CDCl₃) δ: 6.39 (CONH), 4.99 (H-13), 4.79 (H-1"), 4.68(H-4"), 4.66 (H-11), 4.48 (H-1'), 4.46 (H-10), 4.21 (H-3), 3.76 (H-5),3.30 (3"-OCH₃), 3.23 (H-2'), 2.75 (H-8), 2.70 (H-2), 2.29/3'N(CH₃)₂ /,2.26 (H-7a), 2.16, 2.12 and 1.96 (COCH₃), 2.02 (H-7b), 1.94 (H-4), 1.83(H-14a), 1.56 (H-14b), 0.86 (H-15). ¹³ C NMR (75 MHz, CDCl₃) δ: 179.2(C-1), 174.6 (C-9), 171.7, 170.3 and 169.0 (COCH₃), 102.9 (C-1'), 94.9(C-1"), 85.6 (C-6), 80.5 (C-5), 78.3 (C-3), 78.2 (C-11), 76.7 (C-13),74.7 (C-12), 49.2 (3"-OCH₃), 45.1 (C-10), 42.4 (C-2), 40.0/3'N(CH₃)₂ /,39.3 (C-4), 37.3 (C-7), 33.9 (C-8), 21.9 (C-14), 21.1, 20.9 and 20.6(COCH₃), 10.7 (C-15).

EXAMPLE 810-N-(4-bromobenzoyl)-6-deoxy-6,9-epoxy-8(R)-methyl-10-amino-9,10-secoerythromycinA (2d)

To a solution of 10 g (0.013 mole) of (2a) in diethylether (60 ml &NaHCO₃ (8.0 g, 0.095 mole), 4-bromobenzoylchloride solution (4.0 g,0.018 mole) in diethylether (20 ml) was added dropwise within 1 hourunder stirring at a temperature from 0° to 5° C. The reaction mixturewas stirred for further 2 hours at the same temperature, the solvent wasevaporated at a reduced pressure, then CHCl₃ (70 ml) and water (50 ml)were added m the obtained solid residue and then it was extracted at pH8.5. The reaction mixture was evaporated at a reduced pressure and theobtained solid residue (5.0 g) was purified by chromatography on silicagel column by the use of 90:9:1.5 CH₂ Cl₂ :CH₃ OH:conc. NH₄ OH systemyielding TLC homogeneous 4-bromobenzoate (2d) with the followingphysical-chemical constants:

IR (CHCl₃) cm⁻¹ : 1740 (C-1, lactone), 1710 (C-9, lactone), 1640 and1500 (C-10, amide), 1580 (Ph). , 4.91 (H-13), 4.70 (H-1"), ¹ H NMR 9300MHz, CDCl₃) δ: 7.60 (Ph), 7.05 CONH, 4.35 (H-1'), 4.37 (H-10), 4.21(H-3), 3.70 (H-5), 3.67 (H-11), 3.27 (3"-OCH₃), 3.15 (H-2'), 2.91(H-4"), 2.73 (H-8), 2.71 (H-2), 2.26/3'N(CH₃)₂ /, 2.21, (H-7a), 2.10(H-7b), 1.94 (H-4), 1.86 (H-14a), 1.57 (H-14b), 0.89 (H-15). ¹³ C NMR(75 MHz, CDCl₃) δ: 179.6 (C-1), 176.7 (C-9), 165.4 (CONH), 133.8, 131.6,128.9 and 125.8 (Ph), 104.0 (C-1'), 95.0 C-1"), 86.4 (C-6), 81.7 (C-5),79.9 (C-3), 75.6 (C-13), 73.4 (C-11), 74.6 (C-12), 49.4 (3"-OCH₃), 47.3(C-10), 43.2 (C-2), 40.0 /3'N(CH₃)₂ /, 40.0 (C-4), 37.8 (C-7), 34.2(C-8), 22.5 (C-14), 11.2 (C-15). EI-MS (M⁺) 931.

EXAMPLE 91N-(2,3,4-trihydroxy-1,3-dimethyl-hexyl)-amido-10,11,12,13,14,15-hexanor-9-deoxo-6-deoxy-6,9-epoxy-8(R)-methyl-9,10-secoerythromycinA 9(E) Oxime (4a)

The substance (3a) (31 g, 0.041 mole) from Example 1 was dissolved inCH₂ Cl₂ CH₃ OH (1:1, 80 ml), thereto conc. NH₄ OH (350 ml) was added andthe reaction mixture was stirred for 6 hours at room temperature. Thesolution was left to stand overnight and then it was evaporated at areduced pressure and the obtained solid residue was suspended in CH₂Cl₂, filtered and subsequently the filtrate was evaporated to drynessyielding 29.5 g (95%) of TLC (CHCl₃ :CH₃ OH:conc. NH₄ OH, 6:1:0.1)homogeneous product (4a).

IR (CHCl₃) cm⁻¹ : 3420, 2980, 1690, 1650, 1530, 1455, 1380, 1260, 1175,1050. ¹ H NMR (300 MHz, CDCl₃) δ: 7.53 (CONH), 4.93 (H-1"), 4.45 (H-1'),4.20 (H-3), 4.11 (H-10), 3.79 (H-11), 3.66 (H-5), 3.39 (3'-OCH₃), 3.22(H-13), 3.04 (H-8), 2.53 (H-2), 2.29/3'N(CH₃)₂ /, 2.10 (H-7a), 1.97(H-4), 1.79 (H-7b), 1.59 (H-14a), 1.33 (H-14b), 1.04 (H-15). ¹³ C NMR(75 MHz, CDCl₃) δ:174.4 (C-1), 162.0 (C-9), 105.6 (C-1'), 96.2 (C-1"),90.3 (C-6), 86.3 (C-5), 83.0 (C-13), 79.8 (C-3), 75.1 (C-11), 74.9(C-12) 49.3 (3"-OCH₃), 48.6 (C-10), 42.8 (C-2), 41.0 (C-7), 39.8/3'N(CH₃)₂ /, 38.6 (C-4), 32.9 (C-8), 24.8 (C-14), 11.5 (C-15). FAB(MH⁺) 764.4.

EXAMPLE 101N-(2,3,4-trihydroxy-1,3-dimethyl-hexyl)-amido-10,11,12,13,14,15-hexanor-9-deoxo-6-deoxy-6,9-epoxy-8(R)-methyl-9,10-secoerythromycinA 9(E) Oxime (4a)1-N-(2,3,4,-trihydroxy-1,3-dimethyl-hexyl)-amido-10,11,12,13,14,15-hexanor-9-deoxo-6-deoxy-6,9-epoxy-8(S)-methyl-9,10-secoerythromycinA 9(E) Oxime (4b)

Erythromycin A 6,9-imino ether (1) (30 g, 0.041 mole) was dissolved inCH₃ OH (600 ml), Na₂ CO₃ (5.6 g, 0.053 mole) was added thereto and thenthe reaction mixture was stirred under reflux up to the disappearance ofthe starting imino ether (8 hours.) The reaction suspension wasevaporated at a reduced pressure, thereto CH₂ Cl₂ (130 ml) and H₂ O (130ml) were added (pH 11.1) and then it was extracted at pH 8. The combinedorganic extracts were dried over K₂ CO₃ and evaporated whereby 28 g ofsolid residue were obtained. The precipitate was dissolved in CH₃ OH(600 ml), thereto NH₂ OH.HCl (14 g) and Na₂ CO₃ (5.1 g) were added andthen it was stirred under reflux for 3 hours. The reaction mixture wasevaporated to dryness, CH₂ Cl₂ (150 ml) and H₂ O (300 ml) were addedthereto (pH 6.6) and it was extracted by gradient extraction at pH 8 and10. The combined orgainic extracts at pH 10 were dried over K₂ CO₃ andevaporated, whereby 15.6 g of precipitate were obtained. The precipitatewas dissolved in a mixture of CH₃ OH--CH₂ Cl₂ (1:1, 40 ml) and conc. NH₄OH (170 ml) and stirred for 12 hours at room temperature. The reactionmixture was evaporated to dryness and the obtained mixture of productswas separated by chromatography on silica gel column. From 2.2 g of acrude product there were obtained by the use of 6:1:0.1 CHCl₃ :CH₃OH:conc. NH₄ OH system, 1.08 g of a chromatographically homogeneousproduct (4a) (Rf 0.38) with physical-chemical constants as described inExample 9 and 0.80 g of a substance (4b) (Rf 0.26) with the followingphysical-chemical constants:

Compound (4b)

IR (CHCl₃) cm⁻¹ : 3340, 1975, 1685, 1650, 1530, 1450, 1380, 1280, 1240,1160, 1040. ¹ H NMR (300 MHz, CDCl₃) δ: 7.30 (CONH), 4.88 (H-1"), 4.35(H-1'), 4.23 (H-3), 4.15 (H-10), 3.82 (H-11), 3.60 (H-5), 3.29(3"-OCH₃), 3.26 (H-13), 3.14. (H-8), 2.78 (H-7a), 2.52 (H-2),2.29/3'N(CH₃)₂ /, 2.06 (H-4), 1.61 (H-14a), 1.51 (H-7b), 1.37 (H-14b ),1.04 (H- 15). ¹³ C NMR (75 MHz, CDCl₃) δ:173.9 (C-1), 162.7 (C-9), 104.6(C-1'), 95.4 (C-1"), 90.7 (C-6), 86.3 (C-5), 81.6 (C-13), 78.5 (C-3),74.5 (C-11), 74.4 (C-12) 48.8 (3"-OCH₃), 47.4 (C-10), 42.7 (C-2), 42.0(C-7), 39.4 /3'N(CH₃)₂ /, 38.7 (C-4), 33.8 (C-8), 24.1 (C-14), 11.0(C-15). FAB (MH⁺) 764.5.

EXAMPLE 112',4"-O-diacetyl-1-N-(2,4-O-dimethyl-3-hydroxy-1,3-dimethyl-hexyl)-amido-10,11,12,13,14,15-hexanor-9-deoxo-6-deoxy-6,9-epoxy-8(R)-(R)-methyl-9,10-secoerythromycinA 9(E) Acetoxime (4c)

To a solution of the substance (4a) (1.0 g, 0.0013 mole) from example 9in pyridine (40 ml), acetic acid anhydride (4 ml) was added and then itwas left to stand for 10 days at room temperature. The reaction solutionwas poured into a mixture 200 of water and ice (pH 4.8), alkalinizedwith 20% NaOH and then extracted with CHCl₃ at pH 9.0. The combinedorganic extracts were dried over K₂ CO₃ and evaporated at a reducedpressure yielding 1.25 g (98%) of pentaacetate (4c) with the followingphysical-chemical constants:

¹ H NMR (300 MHz, CDCl₃) δ: 6.61 (CONH), 4.94 (H-13), 4.82 (H-1"), 4.80(H-2'), 4.69 (H-4'), 4.58 (H-1'), 4.58 (H-10), 4.55 (H-11), 4.04 (H-3),3.79 (H-5), 3.32 (3"-OCH₃), 3.13 (H-8), 2.59 (H-2), 2.27/3'N(CH₃)₂ /,2.15, 2.12, 2.12, 2.06 and 2.01 (COCH₃), 2.07 (H-7a), 2.03 (H-4), 2.03(H-7b), 1.82 (H-14a), 1.55 (H-14b), 0.90 (H-15). ¹³ C NMR (75 MHz,CDCl₃) δ: 173.4 (C-1), 171.8, 170.6, 170.2, 169.8, and 168.8 (COCH₃),167.2 (C-9), 100.6 (C-1'), 95.5 (C-1"), 91.7 (C-6), 79.8 (C-3), 79.6(C-5), 78.6 (C-11), 75.7 (C-13), 74.7 (C-12) 49.3 (3"-OCH₃), 45.1(C-10), 42.6 (C-2), 40.2/3'N(CH₃)₂ /, 38.8 (C-7), 36.7 (C-4), 33.5(C-8), 21.6 (C-14), 20.9, 20.5, 20.5, 20.4 and 19.4 (COCH₃), 10.5(C-15).

EXAMPLE 124"-O-acetyl-1-N-(2,4-O-diacetyl-3-hydroxy-1,3-dimethyl-hexyl)-amido-10,11,12,13,14,15-hexanor-9-deoxo-6-deoxy-6,9-epoxy-8(R)-methyl-9,10-secoerythromycinA 9(E) Acetoxime (4d)4"-O-acetyl-1-N-(2,4,-O-diacetyl-3-hydroxy-1,3-dimethyl-hexyl)-amido-10,11,12,13,14,15-hexanor-9-deoxo-6-deoxy-6,9-epoxy-8(R)-methyl-9,10-secoerythromycinA 9(E)Oxime (4e)

A solution of 0.5 g (0.0005 mole) of the substance (4c) from Example 11in methanol (20 ml) was stirred for 3 days at room temperature. Thesolvent was separated by evaporation at a reduced presure and theobtained mixture was purified by chromatography on silica gel column bythe use of 6:1:0.1 CHCl₃ :CH₃ OH:conc. NH₄ OH solvent system. After theevaporation of chromatographically homogeneous fractions with Rf 0.47and Rf 0.34, there were obtained 0.213 g of tetraacetate (4d) and 0.151g of triacetate (4e) with the following physical-chemical constants:

Compound (4d)

¹ H NMR (300 MHz, CDCl₃) δ: 7.38 (CONH), 4.94 (H-13), 4.83 (H-1"), 4.66(H-4"), 4.62 (H-11), 4.55 (H-10), 4.44 (H-1'), 4.10 (H-3), 3.80 (H-5),3.32 (3"-OCH₃), 3.35 (H-2'), 3.18 (H-8), 2.76 H-2), 2.30/3'N(CH₃)₂ /,2.07 (H-7a), 2.13, 2.10, 2.09 and 2.03 (COCH₃), 1.90 (H-7b), 1.96 (H-4),1.84 (H-14a), 1.53 (H-14b), 0.90 (H-15). ¹³ C NMR (75 MHz, CDCl₃) δ:174.4 (C-1), 171.1, 170.7, 170.4 and 168.4 (COCH₃), 167.2 (C-9), 105.2(C-1'), 96.9 (C-1"), 92.9 (C-6), 84.5 (C-5), 81.3 (C-3), 78.5 (C-11),75.9 (C-13) 75.0 (C-12), 49.4 (3"-OCH₃), 44.6 (C-10), 41.1 (C-2), 40.1/3'N(CH₃)₂ /, 40.8 (C-7), 38.0 (C-4), 33.8 (C-8), 21.7 (C-14), 20.7,20.5, 20.4 and 19.2 (COCH₃), 10.5 (C-15).

Compound (4e)

¹ H NMR (300 MHz, CDCl₃) δ: 7.24 (CONH), 4.88 (H-13), 4.81 (H-1"), 4.68(H-4"), 4.62 (H-11), 4.50 (H-10), 4.45 (H-1'), 4.07 (H-3), 3.75 (H-5),3.34 (3"-OCH₃), 3.26 (H-2'), 2.98 (H-8), 2.76 (H-2), 2.30/3'N(CH₃)₂ /,2.09 (H-7a), 2.14, 2.09 and 2.03 (COCH₃), 1.92 (H-7b), 1.89 (H-4), 1.83(H-14a), 1.51 (H-14b), 0.89 (H-15). ¹³ C NMR (75 MHz, CDCl₃) δ: 174.6(C-1), 171.1, 170.8, 170.8 (COCH₃), 162.5 (C-9), 104.2 (C-1'), 96.4(C-1"), 90.4 (C-6), 83.9 (C-5), 79.6 (C-3), 78.7 (C-11), 76.1 (C-13)75.1 (C-12), 49.5 (3"-OCH₃), 44.7 (C-10), 43.7 (C-2), 40.1 /3'N(CH₃)₂ /,40.4 (C-7), 39.3 (C-4), 32.5 (C-8), 21.8 (C-14), 20.7, 20.7 and 20.6(COCH₃), 10.7 (C-15).

EXAMPLE 131-N-(2,3,4,-trihydroxy-1,3-dimethyl-hexyl)-amido-10,11,12,13,14,15-hexanor-9-deoxo-6-deoxy-6,9-epoxy-8(R)-methyl-9,10-secoerythromycinA 9(E) Tosyloxime (4f)

The substance (4a) (0.5 g, 0.0007 mole) from Example 9 was suspended inacetone (10 ml) and cooled to 0°-5° C. Solutions of tosylchloride (0.486g, 0.0026 mole) in acetone (10 ml) and NaHCO₃ (0.425 g, 0.0051 mole) inwater (25 ml) were simultaneously added dropwise to the reaction mixtureunder stirring within 30 minutes. The reaction solution was stirred forfurther 12 hours at room temperature, thereafter acetone was evaporatedat a reduced pressure, to the aqueous residue CHCl₃ (30 ml) was addedand then it was extracted by gradient extraction at pH 5.0 and 8.0. Byevaporation of the combined organic extracts at pH 5.0, 0.320 g of crudeproduct (4f) were obtained. By chromatography on silica gel column bythe use of 6:1:0.1 CHCl₃ :CH₃ OH:conc. NH₄ OH, 0.260 g of TLChomogeneous product (4f) were obtained. ¹ H NMR (300 MHz, CDCl₃) δ: 7.80(CONH), 7.62 (Ph), 3.21 (H-13), 4.96 (H-1"), 4.41 (H-1'), 4.17 (H-3),4.11 (H-10), 3.79 (H-11), 3.58 (H-5), 3.39 (H-2'), 3.25 (3"OCH₃), 3.10(H-8), 2.94 (H-4"), 2.55 (H-2), 2.29/3'N(CH₃)₂ /, 2.08 (H-7a), 1.86(H-4), 1.64 (H-7b), 1.56 (H-14a), 1.43 (H-14b), 1.05 (H-15).

EXAMPLE 141-N-(2,3,4-trihydroxy-1,3-dimethyl-hexyl)-amido-10,11,12,13,14,15-hexanor-9-deoxo-9-dihydro-9a-amino-8(R)-methyl-9a-homoerythromycinA (5a)

The crude product (4a) (6.0 g, 0.008 mole) from Example 9 was dissolvedin glacial acetic acid (60 ml), PtO₂ (2.0 g, 83.0% Pt) were added andthen it was hydrogenated at a H₂ pressure of 7×10⁶ Pa under stirringwithin 10 hours. The reaction suspension was filtered, the filtrate wasevaporated at a reduced pressure, H₂ O (100 ml) and CHCl₃ (60 ml) wereadded thereto and subsequently it was extracted by gradient extractionat pH 5.5, 9.0 and 10.5. The combined chloroform extracts at pH 10.5were evaporated at a reduced pressure fielding 4.3 g (73%) of TLChomogeneous product (5a) with the following physical-chemical constants:

IR (CHCl₃) cm⁻¹ : 3400, 2975, 1650, 1535, 1450, 1375, 1165, 1040. ¹ HNMR (300 MHz, CDCl₃) δ: 7.52 (CONH), 4.94 (H-1"), 4.37 (H-1'), 4.26(H-3), 4.17 (H-10), 3.76 (H-11), 3.41 (H-5), 3.28 (3"-OCH3), 3.17(H-13), 2.62 (H-9a), 2.52 (H-2), 2.27/3'N(CH₃)₂ /, 2.20 (H-7a), 2.01(H-4), 1.85 (H-8), 1.55 (H-14a), 1.34 (H-7b), 1.34 (H-14b), 1.05 (H-15).¹³ C NMR (75 MHz, CDCl₃) δ:174.1 (C-1), 106.7 (C-1'), 96.0 (C-1"), 92.3(C-5), 83.8 (C-13), 79.7 (C-3), 75.1 (C-12), 74.8 (C-11) 74.6 (C-6),49.3 (3"-OCH₃), 49.2 (C-10), 49.1 (C-9), 42.8 (C-7), 41.6 (C-2),39.6/3'N(CH₃)₂ /, 37.5 (C-4), 31.0 (C-8), 25.0 (C-14), 11.5 (C-15). FAB(NH⁺) 752.3.

EXAMPLE 151-N-(2,3,4-trihydroxy-1,3-dimethyl-hexyl)-amido-10,11,12,13,14,15-hexanor-9-deoxo-9-dihydro-9a-amino-8(S)-methyl-9a-homoerythromycinA (5b)

The substance (4b) (0.71 g, 0.009 mole) was dissolved in glacial aceticacid (30 ml), PtO₂ (0.350g, 83% Pt) was added and then it washydrogenated under stirring for 10 hours at a H₂ pressure 7×10⁶ Pa. Thereaction mixture was filtered, the filtrate was evaporated to a thickoily residue and the product was isolated by gradient extraction at pH5.5, 9.0 and 10.5 as described in Example 14, whereupon after theevaporation of the combined organic extracts at pH 10.5, 0.260 g (38.0%)of TLC homogeneous title product (5b) were obtained.

¹ H NNR (300 MHz, CDCl₃) δ: 7.63 (CONH), 4.93 (H-1"), 4.40 (H-1'), 4.23(H-3), 4.19 (H-10), 3.75 (H-11), 3.53 (H-5), 3.29 (3"-OCH₃) 3.18 (H-13),2.72 (H-9a), 2.57 (H-9b), 2.52 (H-2), 2.27/3'N(CH₃)₂ /, 1.93 (H-4), 1.78(H-8). 1.57 (H-14a), 1.47 (H-7a), 1.36 (H-14b), 1.23 (H-7b), 1.04(H-15). ¹³ C NMR (75 MHz, CDCl₃) δ: 174.3 (C-1), 107.2 (C-1'), 97.0(C-1"), 92.3 (C-5), 83.8 (C-13), 80.7 (C-3), 75.7 (C-12), 75.2 (C-11),75.2 (C-6), 49.6 (3"-OCH₃), 49.2 (C-9), 49.2 (C-10), 43.7 (C-7), 42.1(C-2), 39.8/3'N(CH₃)₂ /, 37.8 (C-4), 31.3 (C-8), 25.0 (C-14), 11.7(C-15).

EXAMPLE 161-N-(2,3,4-trihydroxy-1,3-dimethyl-hexyl)-amido-10,11,12,13,14,15-hexanor-9-deoxo-9-dihydro-9a-dimethylamino-8(R)-methyl-9a-homoerythromycinA (6a)

To a solution of compound (5a) (1 g, 0.0013 mole) from Example 14 inCHCl₃ (80 ml), 0.2 ml (0.005 mole) of formic acid (98-100%) and 0.232 ml(0.003 mole) of formaldehyde (36%) were added. The pH of the reactionmixture was adjusted to 5.0 (with 2% w/v NaOH) and then it was stirredunder reflux for 9 hours. Subsequently the addition of H₂ O (100 ml),the product was isolated by gradient extraction with CHCl₃ at pH 5.0 and9.5 and the combined organic extracts at pH 9.5 were evaporated at areduced pressure. By chromatography of the obtained product on silicagel column by the use of 6:1:0.1 CHCl₃ :CH₃ OH:conc. NH₄ OH system, 0.63g of TLC homogeneous product (6a) were obtained.

IR (CHCl₃) cm⁻¹ : 3400, 2970, 1650, 1530, 1450, 1375, 1165, 1040. ¹ HNMR (300 MHz, CDCl₃) δ: 7.26 (CONH), 4.91 (H-1"), 4.37 (H-1'), 4.27(H-3), 4.18 (H-10), 3.77 (H-11), 3.41 (H-5), 3.29 (3"-OCH₃), 3.18(H-13), 2.57 (H-2), 2.52 (H-9a), 2.30/3'N(CH₃)₂ /, 9a-N(CH₃)₂ /, 2.20(H-9b), 2.16 (H-4), 2.01 (H-8), 1.56 (H-14a), 1.50 (H-7a), 1.37 (H-14b),1.15 (H-7b), 1.04 (H-15). ¹³ C NMR (75 MHz, CDCl₃) δ: 174.7 (C-1), 106.1(C-1'), 95.4 (C-1"), 90.5 (C-5), 83.3 (C-13), 79.8 (C-3), 74.8 (C-12),74.6 (C-11), 73.7 (C-6), 68.2 (C-9), 49.2 (3"-OCH₃), 48.6 (C-10),45.3/9a-N(CH₃)₂ /, 44.2 (C-7), 41.7 (C-2), 39.6/3'N(CH₃)₂ /, 37.3 (C-4),26.4 (C-8), 24.9 (C-14); 11.5 (C-15). FAB (MH⁺) 780.6.

EXAMPLE 171-N-(2,3,4-trihydroxy-1,3-dimethyl-hexyl)-amido-10,11,12,13,14,15-hexanor-9-deoxo-9-dihydro-9a-dimethylamino-8(S)-methyl-9a-homoerythromycinA (6b)

To a solution of the compound (5b) (0.3 g, 0.0004 mole) from Example 15in CHCl₃ (50 ml), 0.12 ml (0.0032 mole) of formic acid (98-100%) and0.13 ml (0.0016 mole) of formaldehyde (36%) were added. The pH of thereaction mixture was adjusted to 5.0 (with 2% w/v NaOH) and then it wasstirred under reflux for 4 hours. The isolation of the product wasperformed as described in Example 16, yielding after chromatography onsilica gel column by the use of 6:1:0.1 CHCl₃ :CH₃ OH:conc. NH₄ OHsystem 0.150 g of TLC homogeneous product (6b).

¹ H NMR (300 MHz, CDCl₃) δ: 7.58 (CONH), 4.95 (H-1"), 4.41 (H-1'), 4.25(H-3), 4.18 (H-10), 3.76 (H-11), 3.43 (H-5), 3.28 (3"-OCH₃), 3.17(H-13), 2.51 (H-2), 2.27/3'N(CH₃)₂ /, 2.23/9a-N(CH₃)₂ /, 2.06 (H-9b),2.19 (H-4), 1.97 (H-8), 1.57 (H-14a), 1.47 (H-7a), 1.37 (H-14b), 1.16(H-7b), 1.05 (H-15). ¹³ C NMR (75 MHz, CDCl₃) δ: 173.5 (C-1), 106.0(C-1'), 95.3 (C-1"), 91.9 (C-5), 83.2 (C-13), 79.0 (C-3), 74.4 (C-12),74.1 (C-11), 74.2 (C-6), 67.5 (C-9), 48.6 (3"-OCH₃), 48.4 (C-10), 44.9/9-N(CH₃)₂ /, 43.1 (C-7), 40.8 (C-2), 38.9 /3'N(CH₃)₂ /, 36.7 (C-4),25.8 (C-8), 23.9 (C-14), 10.4 (C-15).

EXAMPLE 189-Deoxo-6-deoxy-6,9-epoxy-8(R)-methyl-10,11,12,13,14,15-hexanor-erythromycinA 9(E) Oxime (7a)9-Deoxo-6-deoxy-6,9-epoxy-8(S)-methyl-10,11,12,13,14,15-hexanor-erythromycinA 9(E) Oxime (7b)

The combined chloroform extracts at pH 8 from Example 10 were dried overK₂ CO₃ and evaporated at a reduced pressure yielding 8.0 g of mixture of(7a) and (7b). By chromatography on silica gel column by the use of6:1:0.1 CHCl₃ :CH₃ OH:conc. NH₄ OH system, from 2.0 g of a crude productthere were obtained 0.530 g of substance (7a) with Rf 0.44 and 0.880 gof substance (7b) with 0.39 which were identified by spectrascopicmethods as C-8 stereoisomers.

Compound (7a)

IR (CHCl₃) cm⁻¹ : 3360, 2980, 2940, 1730, 1690, 1650, 1455, 1380, 1245,1165, 1040. ¹ H NMR (300 MHz, CDCl₃) δ: 4.72 (H-1"), 4.44 (H-1'), 4.11(H-3), 3.84 (H-5), 3.67 (1-OCH₃), 3.29 (3"-OCH₃), 3.26 (H-2'), 3.03(H-8), 3.01 (H-4"), 2.84 (H-2), 2.09 ((H-7a), 2.33/3'N(CH₃)₂ /, 1.97(H-4), 2.01 (H-7b). ¹³ C NMR (75 MHz CDCl₃) δ: 176.1 (C-1), 161.8 (C-9),103.8 (C-1'), 95.8 (C-1"), 89.7 (C-6), 81.0 (C-5), 79.8 (C-3), 51.8(1-OCH₃), 49.4 (3"-OCH₃), 39.9 (C-7), 41.7 (C-2), 40.4/3'N(CH₃)₂ /, 37.8(C-4), 33.0 (C-8). FAB (MH⁺) 619.4.

Compound (7b)

IR (CHCl₃) cm⁻¹ : 3360, 2980, 2940, 1730, 1690, 1650, 1455, 1380, 1245,1165, 1040. ¹ H NMR (300 MHz, CDCl₃) δ: 4.61 (H-1"), 4.43 (H-1'), 4.09(H-3), 3.71 (H-5), 3.68 (1-OCH₃), 3.28 (3"-OCH₃), 3.17 (H-8), 2.89(H-7a), 2.74 (H-2), 2.33/3'N(CH₃)₂ /, 2.16 (H-4), 1.47 (H-7b). ¹³ C NMR(75 MHz, CDCl₃) δ:176.0 (C-1), 1.62.9 (C-9), 102.7 (C-1'), 95.1 (C-1")90.4 (C-6), 80.1 (C-5), 79.0 (C-3), 51.6 (1-OCH₃), 49.2 (3"-OCH₃), 42.5(C-7), 41.0 (C-2), 40.3/3'N(CH₃)₂ /, 38.1 (C-4), 34.5 (C-8).

EXAMPLE 199-Deoxo-9-dihydro-9a-amino-8(R)-methyl-10,11,12,13,14,15-hexanor-9a-homoerythromycinA (8a)

The substance (7a) (0.90 g, 0.0015 mole) was dissolved in glacial aceticacid (30 ml), PtO₂ (0.30 g, 83% Pt) was added thereto and then it washydrogenated at H₂ pressure of 6×10⁶ Pa under stirring for 15 hours. Thereaction mixture was filtered, the filtrate was evaporated to a thickoily residue and a product was isolated by gradient extraction at pH5.5, 9.0 and 10.5 as described in Example 14, whereupon after theevaporation of the combined organic extracts at pH 10.5, 0.530 g (60%)of TLC homogeneous title product (8a) were obtained.

¹ H NMR (300 MHz, CDCl₃) δ: 4.64 (H-1"), 4.40 (H-1'), 4.14 (H-3), 3.67(1-OCH₃), 3.54 (H-5), 3.29 (H-3"OCH₃), 2.85 (H-2), 2.74 (H-9a), 2.50(H-9b), 2.30/3'N(CH₃)₂ /, 2.10 (H-4), 1.84 (H-8), 1.44 (H-7a), 1.22(H-7b). ¹³ C NMR (75 MHz, CDCl₃) δ:176.4 (C-1), 104.4 (C-1'), 96.0(C-1"), 85.9 (C-5), 80.3 (C-3), 73.8 (C-6), 51.5 (1-OCH₃), 49.2(3"-OCH₃), 49.1 (C-9), 42.9 (C-7), 41.2 (C-2) 40.2/3'N(CH₃)₂, 37.3(C-4), 31.1 (C-8).

EXAMPLE 209-Deoxo-9-dihydro-9a-amino-8(S)-methyl-10,11,12,13,14,15-hexanor-9a-homoerythromycinA (8b)

The substance (7b) (0.70 g, 0.0011 mole) was dissolved in glacial aceticacid (25 ml), PtO₂ (0.23 g, 83% Pt) was added thereto and then it washydrogenated at H₂ pressure of 6×10⁶ Pa under stirring for 15 hours. Thereaction mixture was filtered, the filtrate was evaporated to a thickoily residue and a product was isolated by gradient extraction at pH5.5, 9.0 and 10.5 as described in Example 14, whereupon after theevaporation of the combined organic extracts at pH 10.5, 0.350 g (52.4%)of TLC homogeneous title product (8b) were obtained.

IR (CHCl₃) cm⁻¹ : 3400, 2975, 2940, 1735, 1580, 1455, 1375, 1260, 1170,1050, 1000. ¹ H NMR (300 MHz, CDCl₃) δ:4.64 (H-1"), 4.37 (H-1'), 4.15(H-3), 4.04 (H-5"), 3.67 (1-OCH₃, 3.60 (H-5'), 3.51 (H-5), 3.37 (H-2'),3.28 (H-3"OCH₃), 2.98 (H-4"), 2.75 (H-2), 2.68 (H-9a), 2.56 (H-9b), 2.54(H-3'), 2.31/3'N(CH₃)₂ /, 1.93 (H-4), 1.79 (H-8), 1.70 (H4'a), 1.47(H-2"b).

EXAMPLE 219-Deoxo-9-dihydro-9a-dimethylamino-8(R)-methyl-10,11,12,13,14,15-hexanor-9a-homoerythromycinA (9a)

To a solution of the substance (8a) (0.3 g, 0.0005 mole) from Example 19in CHCl₃ (50 ml), 0.05 ml (0.0013 mole) of formic acid (98-100%) and0.052 ml (0.0007 mole) of formaldehyde (36%) were added. The pH of thereaction mixture was adjusted to 5.2 (with 2% w/v NaOH) and then it wassifted under reflux for 2.5 hours. The isolation of the product wasperformed as described in Example 16, yielding 0.280 g (89.0%) of TLChomogeneous product (9a).

IR (CHCl₃) cm⁻¹ : 3450, 2975, 2940, 1735, 1465, 1375, 1260, 1200, 1165,1000. ¹ H NMR (300 MHz, CDCl₃) δ: 4.641 (H-1"), 4.43 (H-1'), 4.13 (H-3),4.06 (H-5"), 3.65 (1-OCH₃), 3.64 (H-5), 3.53 (H-5'), 3.30 (H-3"OCH₃),3.27 (H-2'), 2.97 (H-2), 2.53 ((H-3'), 2.29/3'N(CH₃)₂ /, 2.28 (H-2'a),2.24/9a-N(CH₃)₂ /, 2.10 (H-4), 1.96 (H-8), 1.67 (H-7a).

EXAMPLE 229-Deoxo-9-dihydro-9a-dimethylamino-8(S)-methyl-10,11,12,13,14,15-hexanor-9a-homoerythromycinA (9b)

To a solution of a substance (8b) (0.6 g, 0.001 mole) from Example 19 inCHCl₃ (50 ml), 0.1 ml (0.0026 mole) of formic acid (98-100%) and 0.104ml (0.0014 mole) of formaldehyde (36%) were added. The pH of thereaction mixture was adjusted to 5.2 (with 2% w/v NaOH) and then it wasstirred under reflux for 2.5 hours. The isolation of the product wasperformed as described in Example 16, yielding 0.550 g (87.7%) of TLChomogeneous product (9b).

We claim:
 1. A compound of the general formula (I) ##STR7## wherein R₁and R₂ are the same and represent H or CH₃,R₃ and R₄ are different andrepresent H or CH₃, Y is O or NH, and Z is CH₃ orCH(CH₃)CH(OH)COH(CH₃)CH(OH)C₂ H₅ group,or its pharmaceuticallyacceptable addition salts with inorganic or organic acids.
 2. A compoundaccording to claim 1, wherein R₁, R₂ and R₄ are the same and representH, R₃ is CH₃, Y is NH, and Z is CH(CH₃)CH(OH)COH(CH₃)CH(OH)C₂ H₅.
 3. Acompound according to claim 1, wherein R₁, R₂ and R₃ are the same andrepresent H, R₄ is CH₃, Y is NH, and Z is CH(CH₃)CH(OH)COH(CH₃)CH(OH)C₂H₅.
 4. A compound according to claim 1, wherein R₁, R₂ and R₃ are thesame and represent CH₃, R₄ is H, Y is NH, and Z isCH(CH₃)CH(OH)COH(CH₃)CH(OH)C₂ H₅.
 5. A compound according to claim 1,wherein R₁, R₂ and R₄ are the same and represent CH₃, R₃ is H, Y is NH,and Z or CH(CH₃)CH(OH)COH(CH₃)CH(OH)C₂ H₅.
 6. A compound according toclaim 1, wherein R₁, R₂ and R₄ are the same and represent H, R₃ is CH₃,Y is O, and Z is CH₃.
 7. A compound according to claim 1, wherein R₁, R₂and R₃ are the same and represent H, R₄ is CH₃, Y is O, and Z is CH₃. 8.A compound according to claim 1, wherein R₁, R₂ and R₃ are the same andrepresent CH₃, R₄ is H, Y is O, and Z is CH₃.
 9. A compound according toclaim 1, wherein R₁, R₂ and R₄ are the same and represent CH₃, R₃ is H,Y is O, and Z is CH₃.
 10. A compound of the general formula (II)##STR8## wherein X is O or NOR₇, wherein R₇ is H, acyl or arylsulfonylgroup,R₃ and R₄ are different and represent H or CH₃, R₅ and R₆ are thesame or different and represent H or acyl group, Y is O or NH, and Z isCH₃, CH(C₂ H₅)COH(CH₃)CH(OR₈)CH(CH₃)NHR₉ orCH(CH₃)CH(OR₁₀)COH(CH₃)CH(OR₁₁)C₂ H₅ group, R₈ is H or acyl group, R₉ isH, acyl or arylsulfonyl group, and R₁₀ and R₁₁ are the same andrepresent H or acyl group,or its pharmaceutically acceptable additionsalts with inorganic or organic acids.
 11. A compound according to claim10, wherein X and Y are the same and represent O, R₃ is CH₃, R₄, R₅ andR₆ are the same and represent H, Z is CH(C₂H₅)COH(CH₃)CH(OR₈)CH(CH₃)NHR₉ group, wherein R₈ and R₉ are the same andrepresent H.
 12. A compound according to claim 10, wherein X and Y arethe same and represent O, R₃ is CH₃, R₄ is H, R₅ and R₆ are the same andrepresent acetyl group, Z is CH(C₂ H₅)COH(CH₃)CH(OR₈)CH(CH₃)NHR₉ group,wherein R₈ and R₉ are the same and represent acetyl group.
 13. Acompound according to claim 10, wherein X and Y are the same andrepresent O, R₃ is CH₃, R₄ and R₅ are the same and represent H, R₆ isacetyl group, and Z is CH(C₂ H₅)COH(CH₃)CH(OR₈)CH(CH₃)NHR₉ group,wherein R₈ and R₉ are the same and represent acetyl group.
 14. Acompound according to claim 10, wherein X and Y are the same andrepresent O, R₃ is CH₃, R₄, R₅ and R₆ are the same and represent H, andZ is CH(C₂ H₅)COH(CH₃)CH(OR₈)CH(CH₃)NHR₉ group, wherein R₈ is H and R₉is p-bromobenzoyl group.
 15. A compound according to claim 10, wherein Xrepresents NOR₇, wherein R₇ is H, R₃ is CH₃, R₄, R₅ and R₆ are the sameand represent H, Y is O and Z is CH(C₂ H₅)COH(CH₃)CH(OR₈)CH(CH₃)NHR₉group, wherein R₈ and R₉ are the same and represent H.
 16. A compoundaccording to claim 10, wherein X represents NOR₇, wherein R₇ is acetyl,R₃ is CH₃, R₄ is H, R₅ and R₆ are the same and represent acetyl group, Yis O and Z is CH(C₂ H₅)COH(CH₃)CH(OR₈)CH(CH₃)NHR₉ group, wherein R₈ andR₉ are the same and represent acetyl group.
 17. A compound according toclaim 10, wherein X represents NOR₇, wherein R₇ is H, R₃ is CH₃, R₄ andR₅ represent H, R₆ is acetyl group, Y is O and Z is CH(C₂H₅)COH(CH₃)CH(OR₈)CH(CH₃)NHR₉ group, wherein R₈ and R₉ are the same andrepresent acetyl group.
 18. A compound according to claim 10, wherein Xrepresents NOR₇, wherein R₇ is tosyl group, R₃ is CH₃, R₄, R₅ and R₆ arethe same and represent H, Y is O and Z is CH(C₂H₅)COH(CH₃)CH(OR₈)CH(CH₃)NHR₉ group, wherein R₈ is H and R₉ is tosylgroup.
 19. A compound according to claim 10, wherein X represents NOR₇,wherein R₇ is H, R₃ is CH₃, R₄, R₅ and R₆ are the same and represent H,Y is O and Z is CH(C₂ H₅)COH(CH₃)CH(OR₈)CH(CH₃)NHR₉ group, wherein R₈ isH and R₉ is tosyl group.
 20. A compound according to claim 10, wherein Xrepresents NOR₇, wherein R₇ is H, R₃ is H, R₄ is CH₃, Y is O and Z isCH(C₂ H₅)COH(CH₃)CH(OR₈)CH(CH₃)NHR₉ group, wherein R₈ and R₉ are thesame and represent H.
 21. A compound according to claim 10, wherein Xrepresents NOR₇, wherein R₇ is H, R₃ is CH₃, R₄, R₅ and R₆ are the sameand represent H, Y is NH and Z is CH(CH₃)CH(OR₁₀)COH(CH₃)CH(OR₁₁)C₂ H₅group, wherein R₁₀ and R₁₁ are the same and represent H.
 22. A compoundaccording to claim 10, wherein X represents NOR₇, wherein R₇ is acetyl,R₃ is CH₃, R₄ is H, R₅ and R₆ are the same and represent acetyl, Y is NHand Z is CH(CH₃)CH(OR₁₀)COH(CH₃)CH(OR₁₁)C₂ H₅ group, wherein R₁₀ and R₁₁are the same and represent acetyl.
 23. A compound according to claim 10,wherein X represents NOR₇, wherein R₇ is acetyl, R₃ is CH₃, R₄ and R₅are the same and represent H, R₆ is acetyl group, Y is NH and Z isCH(CH₃)CH(OR₁₀)COH(CH₃)CH(OR₁₁)C₂ H₅ group, wherein R₁₀ and R₁₁ are thesame and represent acetyl.
 24. A compound according to claim 10, whereinX represents NOR₇, wherein R₇ is H, R₃ is CH₃, R₄ and R₅ are the sameand represent H, R₆ is acetyl group, Y is NH and Z isCH(CH₃)CH(OR₁₀)COH(CH₃)CH(OR₁₁)C₂ H₅ group, wherein R₁₀ and R₁₁ are thesame and represent acetyl.
 25. A compound according to claim 10, whereinX represents NOR₇, wherein R₇ is tosyl, R₃ is CH₃, R₄, R₅ and R₆ are thesame and represent H, Y is NH and Z is CH(CH₃)CH(OR₁₀)COH(CH₃)CH(OR₁₁)C₂H₅ group, wherein R₁₀ and R₁₁ are the same and represent H.
 26. Acompound according to claim 10, wherein X represents NOR₇, wherein R₇ isH, R₃, R₅, and R₆ are the same and represent H, R₄ is CH₃, Y is NH and Zis CH(CH₃)CH(OR₁₀)COH(CH₃)CH(OR₁₁)C₂ H₅ group, wherein R₁₀ and R₁₁ arethe same and represent H.
 27. A compound according to claim 10, whereinX represents NOR₇, wherein R₇ is H, R₃ is CH₃, R₄, R₅ and R₆ and R₆ arethe same and represent H, Y is O and Z is CH₃.
 28. A compound accordingto claim 10, wherein X represents NOR₇, wherein R₇ is H, R₃, R₅, and R₆are the same and represent H, R₄ is CH₃, Y is O and Z is CH₃.
 29. Aprocess for the preparation of compounds of the general formula (I)##STR9## wherein R₁ and R₂ are the same and represent H or CH₃,R₃ and R₄are different and represent H or CH₃, Y is O or NH, and Z is CH₃ orCH(CH₃)CH(OH)COH(CH₃)CH(OH)C₂ H₅ group,or their pharmaceuticallyacceptable addition salts with inorganic or organic acids, characterizedin that erythromycin A imino ether of formula (III), ##STR10## issubjected A) to the action of acetic acid under the conditions of thehydrolysis of the imino group and then optionally to N- or O-acylationor both with acid anhydrides or chlorides and then optionally tomethanolysis, or B) to the reaction with hydroxylamine hydrochloride inthe presence of appropriate inorganic or organic bases, in a solventinert to the reaction, in one or two reaction steps and then optionallyB1) to the action of appropriate inorganic or organic acids under theconditions of the hydrolysis of the hydroxyimino group and thenoptionally to N- or O-acylation or both with acid anhydrides orchlorides and then optionally B3) to the action of appropriate organicor inorganic basis under the conditions of internal amine acylation andthen optionally to N- or O-acylation or both with acid anhydrides orchlorides and then optionally to methanolysis, yielding compounds of thegeneral formula (II), ##STR11## wherein X is O or NOR₇, wherein R₇ is H,acyl or arylsulfonyl group, R₃ and R₄ are different and represent H orCH₃, R₅ and R₆ are the same or different and represent H or acyl group,Y is O or NH, and Z is CH₃, CH(C₂ H₅)COH(CH₃)CH(OR₈)CH(CH₃)NH₉ orCH(CH₃)CH(OR₁₀)COH(CH₃)CH(OR₁₁)C₂ H₅ group, R₈ is H or acyl group, R₉ isH, acyl or arylsulfonyl group, and R₁₀ and R₁₁ are the same andrepresent H or acyl group,and their pharmaceutically acceptable additionsalts with inorganic or organic acids, which optionally are subjected toa catalytic reduction in a solvent inert to the reaction, and thenoptionally to reductive N-alkylation with appropriate alkylation agentsin the presence of appropriate reductive agents, yielding compounds ofthe general formula (I), wherein R₁, R₂, R₃, R₄, Y and Z have theabovementioned meanings.
 30. A process according to claim 29,characterized in that erythromycin A imino ether of formula (III) issubjected to the action of acetic acid under the conditions ofhydrolysis of imino group at room temperature within 3 days.
 31. Aprocess according to claim 29, characterized in that the reaction oferythromycin A imino ether of formula (III) with hydroxylaminehydrochloride is performed at a temperature from 25° to 70° C.
 32. Aprocess according to claim 31, characterized in that the appropriateinorganic or organic bases are sodium carbonate, potassium carbonate orpyridine.
 33. A process according to claim 31, characterized in that thesolvent inert to the reaction is methanol or pyridine.
 34. A processaccording to claim 29, characterized in that N- and/or O-acylation of acompound of the general formula (II) ##STR12## wherein X is O or NOR₇,wherein R₇ is H,R₃ is CH₃, and R₄ is H or R₃ is H and R₄ is CH₃, R₅ andR₆ are the same and represent H, Y is O or NH, and Z is, CH(C₂H₅)COH(CH₃)CH(OR₈)CH(CH₃)NHR₉ or CH(CH₃)CH(OR₁₀)COH(CH₃)CH(OR₁₁)C₂ H₅group, wherein R₈, R₉, R₁₀ and R₁₁ are the same and represent H,isperformed with acetic acid anhydride in pyridine at room temperature, orwith tosylchloride in acetone at a temperature from 0° to 5° C., or with4-bromobenzoyl chloride in diethylether at a temperature from 0° to 5°C.
 35. A process according to claim 34, characterized in that a compoundof the general formula (II),wherein X is O or NOR₇, wherein R₇ is acetylgroup, R₃ is CH₃, and R₄ is H or R₃ is H and R₄ is CH₃, R₅ and R₆ arethe same and represent acetyl group, Y is O or NH, and Z is, CH(C₂H₅)COH(CH₃)CH(OR₈)CH(CH₃)NHR₉ or CH(CH₃)CH(OR₁₀)COH(CH₃)CH(OR₁₁)C₂ H₅group, wherein R₈, R₉, R₁₀ and R₁₁ are the same and represent acetylgroup,is subjected optionally to methanolysis yielding a compound of thegeneral formula (II), wherein X is O or NOR₇, wherein R₇ is H or acetylgroup, R₃ is CH₃, and R₄ is H or R₃ is H and R₄ is CH₃, R₅ is H, R₆ isacetyl group, Y is O or NH, and Z is, CH(C₂H₅)COH(CH₃)CH(OR₈)CH(CH₃)NHR₉ or CH(CH₃)CH(OR₁₀)COH(CH₃)CH(OR₁₁)C₂ H₅group, wherein R₈, R₉, R₁₀ and R₁₁ are the same and represent acetylgroup.
 36. A process according to claim 29, characterized in that theappropriate inorganic or organic acids under the conditions ofhydrolysis of hydroxyimino group are HCl or CH₃ COOH.
 37. A processaccording to claim 29, characterized in that the appropriate inorganicor organic bases under the conditions of internal amine acylation areammonium hydroxide, sodium hydroxide, potassium hydroxide ortriethylamine.
 38. A process according to claim 29, characterized inthat the catalytic reduction in a solvent inert to the reaction isperformed in the presence of noble metals or their oxides as catalystsat room temperature and at a hydrogen pressure from 5×10⁵ to 7×10⁶ Pa.39. A process according to claim 38, characterized in that the saidcatalyst is platinum (IV) oxide.
 40. A process according to claim 38,characterized in that the solvent inert to the reaction is glacialacetic acid.
 41. A process according to claim 29, characterized in thatthe reductive N-alkylation of compound of the general formula(I),wherein R₁ and R₂ are the same and represent H, R₃ is CH₃, and R₄ isH or R₃ is H and R₄ is CH₃, Y is NH, and Z is, CH₃ orCH(CH₃)CH(OH)COH(CH₃)CH(OH)C₂ H₅ group,or their pharmaceuticallyacceptable addition salts with inorganic or organic acids, is performedwith appropriate alkylation agents in the presence of appropriatereductive agents in a solvent inert to the reaction at refluxtemperature, yielding compounds of the general formula (I), wherein R₁and R₂ are the same and represent CH₃, R₃ is CH₃, and R₄ is H or R₃ is Hand R₄ is CH₃, Y is NH, and Z is, CH₃ or CH(CH₃)CH(OH)COH(CH₃)CH(OH)C₂H₅ group,or their pharmaceutically acceptable addition salts withinorganic or organic acids.
 42. A process according to claim 41,characterized in that an appropriate alkylation agent for the reductivealkylation process is an aldehyde.
 43. A process according to claim 42,characterized in that an appropriate aldehyde is formaldehyde.
 44. Aprocess according to claim 41, characterized in that an appropriatereductive agent is formic acid.
 45. A process according to claim 41,characterized in that a solvent inert to the reaction is chloroform.